1 American Gastroenterological Association Institute Technical Review on the Pharmacological Management of Irritable Bowel Syndrome: An Update for 2019 Lin Chang, MD, AGAF 1 Anthony Lembo, MD, AGAF 2 Shahnaz Sultan MD, MHSc, AGAF 3 1. G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 2. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02214 3. Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN 55455 Address for Correspondence: Chair, Clinical Guidelines Committee, American Gastroenterological Association National Office, 4930 Del Ray Avenue Bethesda, Maryland 20814 E-mail: [email protected]Telephone: (301) 941-2618 Manuscript Word Count: References: Tables and Figures: eTables and eFigures (in the supplement) Keywords: irritable bowel syndrome, treatment, symptoms, quality of life, randomized controlled trials, meta-analysis, linaclotide, plecanatide, lubiprostone, polyethylene glycol, anti-diarrheals, rifaximin, eluxadoline, alosetron, antispasmodics, tricyclic antidepressants, selective serotonin reuptake inhibitors Disclosures and Conflicts of Interest: Lin Chang has served as a member of the scientific advisory board for Alnylam, Arena, Ardelyx, Bioamerica, IM HealthSciences, Ironwood, Orpho-Med, Ritter, Salix, and Synergy. She has served as a consultant for Allergan. She has received research support from the National Institute of Health, Ardelyx, Alnylam and Vanda. Anthony Lembo has served as a member of the scientific advisory board for Arena, Ardelyx, Bioamerica, IM HealthSciences, Ironwood, Orpho-Med, Ritter, Salix, Shire, Allergan and Vanda. Shahnaz Sultan is supported by the National Heart, Lung, and Blood Institute at the National Institute of Health for Asthma Guideline Development. She has received research support from the Veterans Affairs Health Care System Health Services Research and Development VA Career Development Award. Acknowledgements: The authors sincerely thank Kellee Kaulback, Medical Information Officer, Health Quality Ontario, for helping in the literature search for this technical review.
29
Embed
American Gastroenterological Association Institute ...€¦ · discontinuation. The minimal clinically meaningful improvement (often referred to as the smallest difference that patients
This document is posted to help you gain knowledge. Please leave a comment to let me know what you think about it! Share it to your friends and learn new things together.
Transcript
1
American Gastroenterological Association Institute Technical Review on the Pharmacological Management of Irritable Bowel Syndrome: An Update for 2019
Lin Chang, MD, AGAF1 Anthony Lembo, MD, AGAF2 Shahnaz Sultan MD, MHSc, AGAF3 1. G. Oppenheimer Center for Neurobiology of Stress and Resilience, Vatche and Tamar Manoukian
Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095
2. Division of Gastroenterology, Beth Israel Deaconess Medical Center, Boston, MA 02214 3. Division of Gastroenterology, Hepatology, and Nutrition, University of Minnesota, Minneapolis Veterans Affairs Healthcare System, Minneapolis, MN 55455 Address for Correspondence: Chair, Clinical Guidelines Committee, American Gastroenterological Association National Office, 4930 Del Ray Avenue Bethesda, Maryland 20814 E-mail: [email protected] Telephone: (301) 941-2618 Manuscript Word Count: References: Tables and Figures: eTables and eFigures (in the supplement) Keywords: irritable bowel syndrome, treatment, symptoms, quality of life, randomized controlled trials, meta-analysis, linaclotide, plecanatide, lubiprostone, polyethylene glycol, anti-diarrheals, rifaximin, eluxadoline, alosetron, antispasmodics, tricyclic antidepressants, selective serotonin reuptake inhibitors Disclosures and Conflicts of Interest: Lin Chang has served as a member of the scientific advisory board for Alnylam, Arena, Ardelyx, Bioamerica, IM HealthSciences, Ironwood, Orpho-Med, Ritter, Salix, and Synergy. She has served as a consultant for Allergan. She has received research support from the National Institute of Health, Ardelyx, Alnylam and Vanda. Anthony Lembo has served as a member of the scientific advisory board for Arena, Ardelyx, Bioamerica, IM HealthSciences, Ironwood, Orpho-Med, Ritter, Salix, Shire, Allergan and Vanda. Shahnaz Sultan is supported by the National Heart, Lung, and Blood Institute at the National Institute of Health for Asthma Guideline Development. She has received research support from the Veterans Affairs Health Care System Health Services Research and Development VA Career Development Award. Acknowledgements: The authors sincerely thank Kellee Kaulback, Medical Information Officer, Health Quality Ontario, for helping in the literature search for this technical review.
0.01–0.43) and global improvement in symptoms (RR, 0.73; 95% CI, 0.29–1.86). No improvement in
urgency symptoms was noted and there was no data on IBS-QOL or adverse events. The overall
certainty in evidence for loperamide was VERY LOW.
Discussion
There was a lack of beneficial effect on global improvement of symptoms of IBS and urgency but
improvement in abdominal pain and stool consistency. Improvements in these symptoms occurred
within 3 to 5 weeks of starting treatment, and details of how this was determined were poorly
described. However, this review was based on only 2 very small studies. Both studies were
published in 1987 and were conducted at a time when there was less guidance on the conduct of
high-quality clinical trials. Loperamide has proven efficacy in reducing diarrhea, but there is a lack
of data evaluating its efficacy in relieving individual gastrointestinal symptoms, such as abdominal
pain, in IBS. It is also not clear if loperamide should be only recommended in IBS-D or also in IBS-M,
presumably during a diarrheal phase. The optimal dose and method of using loperamide (e.g., as
needed, daily, after a certain number of diarrheal stools, etc.) is not known and potentially can vary
between patients based on their symptom patterns.
Tricylic antidepressants (TCAs) for IBS
TCAs have been used to treat IBS symptoms due to their peripheral and central (i.e., supraspinal
and spinal) actions which can affect motility, secretion and sensation. IBS and other functional GI
disorders have been redefined in Rome IV as disorders of gut-brain interactions, characterized by
any combination of motility disturbance, visceral hypersensitivity, altered mucosal and immune
function, altered gut microbiota, and altered central nervous system (CNS) processing.61 Consistent
with this redefinition and based on the fact that TCAs and other antidepressants have physiologic
19
effects separate from the effect on mood, these agents have been relabeled as gut-brain
neuromodulators.62
Summary of the evidence
The efficacy of TCAs in IBS was previously evaluated in the prior technical review based on eight
placebo-controlled RCTs in 523 patients (TCAs 297; placebo 122).12 All but one study enrolled
multiple IBS bowel habit subtypes. The type of TCA studied included amitriptyline (n=3),
desipramine (n=2), trimipramine (n=1), imipramine (n=1), and doxepin (n=1). The dose of the TCA
varied from 10 mg to up to 150 mg and most studies used greater than 50 mg per day. Global
assessments differed among the trials and abdominal pain response was assessed in 4 trials.
Compared to placebo, TCAs were associated with global symptom relief (RR 0.67; 95% CI 0.54 to
0.82) and abdominal pain relief (RR 0.76 to 0.94). However, the quality of evidence was rated
down due to indirectness, risk of bias, and imprecision. Based on data from 22 clinical trials in
depression (as long-term high quality data on adverse events with TCAs in IBS was not available),
TCAs showed a significantly higher rate of withdrawals due to side effects compared to placebo (RR
2.11; 95% CI 1.35 to 3.28). The overall certainty in evidence for TCAs was LOW.
Discussion
TCAs were associated with greater responses of adequate relief and abdominal pain relief
compared to placebo, however only global relief response met the threshold for being clinically
meaningful. The beneficial effects of TCAs on IBS symptoms appear to be independent of effects on
depression and may take several weeks. Most studies evaluated higher doses of TCAs (i.e. 50 mg
and higher) than those used in clinical practice. There was one study demonstrating that
amitriptyline 10 mg at bedtime had greater efficacy that placebo in patients with IBS-D.63 TCAs have
multiple actions including inhibition of serotonin and noradrenergic reuptake and blockade of
muscarinic 1, 1 adrenergic, and histamine 1 receptors.62 These effects are beneficial (e.g., reduce
diarrhea and abdominal pain) but also can cause adverse events (e.g. dry mouth, sedation and
constipation). Therefore, the selection of TCA should be based on the patient’s symptom
presentation.
Selective serotonin reuptake inhibitors (SSRIs) for IBS
SSRIs are approved for the treatment of mood disorders, such as anxiety and depression, but are
also used in clinical practice to treat chronic pain conditions. SSRIs selectively inhibit the reuptake
of 5-HT at presynaptic nerve endings, which results in an increased synaptic concentration of 5-HT.
The use of SSRIs in IBS has been of significant interest since IBS is considered a brain-gut disorder
and these agents have centrally mediated effects and increase gastric and intestinal motility,
20
although they do not appear to have a major impact on visceral sensation.62
Summary of the evidence
The efficacy of SSRIs in IBS was studied in seven RCTs,63-69 Most of the studies enrolled a mixture of
all three main bowel habit subtypes. Patients with current psychiatric disease were generally
excluded. Duration of treatment ranged from 6 weeks to 12 weeks. Different SSRIs were evaluated:
fluoxetine 20 mg daily,63, 65 paroxetine 10 mg daily that could be increased,70 paroxetine-CR 12.5-50
mg daily67 and three studies used citalopram at a starting dose of 20 mg that was increased to 40
mg daily after two,69 three,64 or four66 weeks. Compared to placebo, SSRIs showed possible
improvement in symptom relief (RR 0.74; 95% CI 0.52 to 1.06) and in abdominal pain or
discomfort, however the upper boundary of the confidence interval suggested worsening
symptoms of global relief or abdominal pain. The certainty in evidence for this outcome was rated
as low due to serious inconsistency and imprecision. Two studies compared changes in IBS-specific
QOL between the SSRI and placebo groups.66, 70 One study found a significantly greater
improvement in food avoidance score70 and the other study did not detect any differences.66 The
other critical or important outcomes could not be assessed based on the available data. There were
no long-term, data with SSRIs in IBS or depression to assess adverse events leading to treatment
withdrawal.
Discussion
SSRIs did not significantly improve global symptoms or abdominal pain in IBS although the overall
certainty in evidence is low. The ACG IBS Task Force rated the quality of evidence that SSRIs
improve overall symptoms in IBS as low.26 This meta-analysis differed from ours because their
assessment was based on pooling studies that reported either a global assessment of IBS
symptoms, improvement in abdominal pain or discomfort, or overall disease-specific QOL. Multiple
factors, including those arising from central and peripheral processes, contribute to the severity of
IBS symptoms. In some patients, SSRIs may improve the perception of overall IBS symptoms and
well-being by improving GI symptoms, coexistent alterations in mood and extraintestinal
symptoms.71 It is possible that serotonin-norepinephrine reuptake inhibitors (SNRIs) may have a
greater effect on abdominal pain in IBS due to their effects on both serotonin and norepinephrine
reuptake. SNRIs have been shown to be efficacious in other pain conditions but clinical trials in IBS
are lacking.62
Antispasmodics for IBS
Antispasmodics are commonly used in clinical practice to reduce abdominal pain associated with
IBS. Though a pharmacologically diverse class, anti-spasmodics are thought to relieve IBS
21
symptoms by reducing smooth muscle contraction and possibly visceral hypersensitivity.72 Of the
antispasmodics studied, only hyoscine, dicyclomine, and peppermint oil are available in the United
States.
Summary of evidence
This was based on a Cochrane Review that included 22 RCTs evaluating 1,983 IBS patients
(antispasmodics 1008; placebo 1975).73 Twelve different antispasmodics were assessed. There
was considerable variation between the studies concerning diagnostic and inclusion criteria, dosing
schedule and study endpoints. Compared to placebo, there were a significantly greater proportion
of patients taking antispasmodics who had adequate global relief of IBS symptoms (RR of 0.67; 95%
CI 0.55 to 0.80). The overall certainty in evidence, however, was low due to the serious risk of bias
and publication bias. Likewise, compared to placebo, anti-spasmodics showed improvement in
abdominal pain with a RR 0.74 (95% CI 0.59 to 0.93. For this outcome, the certainty in evidence
was very low due to risk of bias, publication bias, and imprecision (the upper boundary of the CI did
not cross our minimal clinically important threshold). The effect of individual antispasmodics was
difficult to interpret due to the small number of studies evaluated for each of the drugs. The most
common adverse events reported were dry mouth, dizziness, and blurred vision, but no serious
adverse events reported. We did not include adverse events leading to discontinuation due to the
lack consistent reporting.
Discussion
Antispasmodics include a wide array of pharmacological therapies that been used clinically for
many years but have not been subjected to rigorous large multicenter trials. There was
considerable variation among the trials and the quality of the studies was generally low. However,
antispasmodics were significantly associated with a greater relief of global symptoms and
abdominal pain, although the latter did not meet our criteria for being clinically meaningful. A
Cochrane Review73 found a beneficial effect for antispasmodics over placebo for improvement in
abdominal pain and global assessment. More recently, the ACG IBS Task Force recently rated the
quality of evidence for antispasmodics in the treatment of overall symptom improvement in IBS as
very low.26 It is not clear if antispasmodics are more efficacious in specific IBS subtypes but its
regular use in constipation may be limited due to its anticholinergic effects. While these
medications are often recommended for treatment of post-prandial symptoms in IBS, this has not
been specifically studied in RCTs.
EVIDENCE GAPS
22
Since the 2014 technical review, the Rome IV diagnostic criteria for IBS was published in 2016.32
The Rome IV criteria differ from the Rome III criteria25 in that abdominal discomfort has been
deleted from the definition and abdominal pain now is required to be present at least 1 day per
week on average during the preceding 3 months.32 Based on these changes fewer individuals meet
the Rome IV criteria for IBS compared to the Rome III criteria.74 However, for the purpose of RCTs
in IBS, which generally measure changes in abdominal pain, the Rome IV criteria are more
applicable. Nonetheless, it is not known whether these changes to the IBS diagnostic criteria would
alter the efficacy and safety of IBS treatments in RCTs.
Responder definitions have varied in multicenter IBS RCTs until the establishment of FDA
composite primary endpoints for IBS-C and IBS-D in 2012,34 which now allows greater
standardization of the efficacy of IBS treatments than in the past. However, these endpoints were
meant to serve as interim primary endpoints while a patient reported outcome (PRO) instrument
was being developed as recommended by the FDA guidance for PROs.75 Efforts to create a FDA
approved IBS PRO are ongoing but have not been completed. The FDA recommended enrollment
criteria and interim primary endpoints for IBS-C and IBS-D but not IBS-M. There continues to be a
lack of studies focusing on IBS-M and no consensus on the optimal primary endpoint for this bowel
habit subgroup. With respect to therapeutic agents that target abdominal pain relief without
significant effects on bowel habits, there is no established consensus on the inclusion and exclusion
criteria regarding bowel symptoms and treatment that normalizes bowel habits without an effect
on abdominal pain (e.g. anti-diarrheals, laxatives).
As stated in the 2014 technical review, a continued unmet need in IBS clinical trials is the lack of a
biomarker that can embody the different pathophysiologic mechanisms of IBS or that can reliably
predict treatment response to medications that have different predominant mechanisms of action
(e.g., normalizing bowel habits, visceral analgesic). However, a recent retrospective analysis of
almost 600 women with IBS-C undergoing a 12-week RCT with renzapride found that baseline
variation in abdominal pain, maximum baseline pain severity, and placebo response in study week
2 or 3 were associated with a response to placebo. Factors associated with a lack of response to
placebo were number of baseline CSBMs and final baseline pain ratings.76
Lastly, our current and previous technical reviews did not include non-pharmacologic interventions
which were beyond the scope of this review. Dietary modification, behavioral treatments, and
probiotics have shown beneficial effects in IBS patients and should be considered on an individual
basis.
23
CONCLUSION
In this updated technical review of pharmacologic treatment for IBS, we evaluated the efficacy and
safety of linaclotide and plecanatide in IBS-C and eluxadoline and retreatment with rifaximin in IBS-
D. We incorporated recent data from a multicenter, RCT conducted predominantly in China
evaluating the efficacy of linaclotide vs. placebo.23 We evaluated the effect of treatment on global
assessments, which were considered critical outcomes as well as individual symptom responses,
HRQOL and adverse events leading to treatment withdrawal, which were considered important
outcomes. The quality of evidence across all critical outcomes for linaclotide was high and was
moderate for plecanatide, eluxadoline and retreatment with rifaximin. In addition, this technical
review summarized the key findings from the 2014 technical review that evaluated the efficacy and
safety of lubiprostone and PEG laxatives in IBS-C, single course of rifaximin, alosetron, and
loperamide in IBS-D and TCAs, SSRIs and antispasmodics in IBS.12 Using the GRADE process in both
technical reviews allowed us to rate the quality of evidence and provide greater transparency and
explicitness about the comparators used and outcomes measured. To weigh the trade-offs involved
with different interventions, the GRADE process presents the absolute risk differences for both
beneficial outcomes and harms. This technical review provided evidence of IBS treatment efficacy
and harm in a structured manner and was used to inform the accompanying IBS Guideline Update.
24
25
References
1. Lovell RM, Ford AC. Global prevalence of and risk factors for irritable bowel syndrome: a meta-analysis. Clin Gastroenterol Hepatol 2012;10:712-721 e4.
2. Monnikes H. Quality of life in patients with irritable bowel syndrome. J Clin Gastroenterol 2011;45 Suppl:S98-101.
3. Lea R, Whorwell PJ. Quality of life in irritable bowel syndrome. Pharmacoeconomics 2001;19:643-53.
4. Singh P, Agnihotri A, Pathak MK, et al. Psychiatric, somatic and other functional gastrointestinal disorders in patients with irritable bowel syndrome at a tertiary care center. J Neurogastroenterol Motil 2012;18:324-31.
5. Nellesen D, Yee K, Chawla A, et al. A systematic review of the economic and humanistic burden of illness in irritable bowel syndrome and chronic constipation. J Manag Care Pharm 2013;19:755-64.
6. Drossman DA, Li Z, Andruzzi E, et al. U.S. householder survey of functional gastrointestinal disorders. Prevalence, sociodemography, and health impact. Dig Dis Sci 1993;38:1569-80.
7. Frandemark A, Tornblom H, Jakobsson S, et al. Work Productivity and Activity Impairment in Irritable Bowel Syndrome (IBS): A Multifaceted Problem. Am J Gastroenterol 2018;113:1540-1549.
8. Pare P, Gray J, Lam S, et al. Health-related quality of life, work productivity, and health care resource utilization of subjects with irritable bowel syndrome: baseline results from LOGIC (Longitudinal Outcomes Study of Gastrointestinal Symptoms in Canada), a naturalistic study. Clin Ther 2006;28:1726-35; discussion 1710-1.
9. Hungin AP, Whorwell PJ, Tack J, et al. The prevalence, patterns and impact of irritable bowel syndrome: an international survey of 40,000 subjects. Aliment Pharmacol Ther 2003;17:643-50.
10. Hungin AP, Chang L, Locke GR, et al. Irritable bowel syndrome in the United States: prevalence, symptom patterns and impact. Aliment Pharmacol Ther 2005;21:1365-75.
11. Ballou S, McMahon C, Lee H, et al. The impact of Irritable Bowel Syndrome on quality of life and daily activities, a comparison between subtypes: insight from the IBS in America Survey. Gastroenterology 2019;156.
12. Chang L, Lembo A, Sultan S. American Gastroenterological Association Institute Technical Review on the pharmacological management of irritable bowel syndrome. Gastroenterology 2014;147:1149-72 e2.
13. Weinberg DS, Smalley W, Heidelbaugh JJ, et al. American Gastroenterological Association Institute Guideline on the pharmacological management of irritable bowel syndrome. Gastroenterology 2014;147:1146-8.
14. Brozek J, Nowak A, Kuntsman P, et al. GRADEpro Guideline Development Tool. 15. Drossman D, Morris CB, Hu Y, et al. Characterization of health related quality of life
(HRQOL) for patients with functional bowel disorder (FBD) and its response to treatment. Am J Gastroenterol 2007;102:1442-53.
16. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0. In: Higgins JPT GS, ed: The Cochrane Collaboration, 2011.
26
17. Silos-Santiago I, Hannig G, Eutamene H, et al. Gastrointestinal pain: unraveling a novel endogenous pathway through uroguanylin/guanylate cyclase-C/cGMP activation. Pain 2013;154:1820-30.
18. Hannig G, Tchernychev B, Kurtz CB, et al. Guanylate cyclase-C/cGMP: an emerging pathway in the regulation of visceral pain. Front Mol Neurosci 2014;7:31.
19. Castro J, Harrington AM, Hughes PA, et al. Linaclotide inhibits colonic nociceptors and relieves abdominal pain via guanylate cyclase-C and extracellular cyclic guanosine 3',5'-monophosphate. Gastroenterology 2013;145:1334-46 e1-11.
20. Chey WD, Lembo AJ, Lavins BJ, et al. Linaclotide for irritable bowel syndrome with constipation: a 26-week, randomized, double-blind, placebo-controlled trial to evaluate efficacy and safety. The American journal of gastroenterology 2012;107:1702-12.
21. Rao S, Lembo AJ, Shiff SJ, et al. A 12-week, randomized, controlled trial with a 4-week randomized withdrawal period to evaluate the efficacy and safety of linaclotide in irritable bowel syndrome with constipation. The American journal of gastroenterology 2012;107:1714-24; quiz p.1725.
22. Johnston JM, Kurtz CB, Macdougall JE, et al. Linaclotide improves abdominal pain and bowel habits in a phase IIb study of patients with irritable bowel syndrome with constipation. Gastroenterology 2010;139:1877-1886 e2.
23. Yang Y, Fang J, Guo X, et al. Linaclotide in irritable bowel syndrome with constipation: A Phase 3 randomized trial in China and other regions. J Gastroenterol Hepatol 2018;33:980-989.
24. Thompson WG, Longstreth GF, Drossman DA, et al. Functional bowel disorders and functional abdominal pain. Gut 1999;45 Suppl 2:II43-7.
26. Ford AC, Moayyedi P, Chey WD, et al. American College of Gastroenterology Monograph on Management of Irritable Bowel Syndrome. Am J Gastroenterol 2018;113:1-18.
27. Black CJ, Burr NE, Quigley EMM, et al. Efficacy of Secretagogues in Patients With Irritable Bowel Syndrome With Constipation: Systematic Review and Network Meta-analysis. Gastroenterology 2018;155:1753-1763.
28. Shah ED, Kim HM, Schoenfeld P. Efficacy and Tolerability of Guanylate Cyclase-C Agonists for Irritable Bowel Syndrome with Constipation and Chronic Idiopathic Constipation: A Systematic Review and Meta-Analysis. Am J Gastroenterol 2018;113:329-338.
29. Brancale A, Shailubhai K, Ferla S, et al. Therapeutically targeting guanylate cyclase-C: computational modeling of plecanatide, a uroguanylin analog. Pharmacol Res Perspect 2017;5:e00295.
30. Boulete IM, Thadi A, Beaufrand C, et al. Oral treatment with plecanatide or dolcanatide attenuates visceral hypersensitivity via activation of guanylate cyclase-C in rat models. World J Gastroenterol 2018;24:1888-1900.
31. Brenner DM, Fogel R, Dorn SD, et al. Efficacy, safety, and tolerability of plecanatide in patients with irritable bowel syndrome with constipation: results of two phase 3 randomized clinical trials. Am J Gastroenterol 2018;113:735-745.
32. Mearin F, Lacy BE, Chang L, et al. Bowel Disorders. Gastroenterology 2016;150:1393-1407.
33. Lewis SJ, Heaton KW. Stool form scale as a useful guide to intestinal transit time. Scand J Gastroenterol 1997;32:920-4.
27
34. (CDER) FaDACfDEaR. Guidance for Industry, Irritable Bowel Syndrome - Clinical Evaluation of Drug for Treatment. 2012. http://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
35. Miner P, DeLuca R, La Portilla M, et al. Plecanatide, a novel uroguanylin analog: a 12-week, randomized, double-blind, placebo-controlled, dose-ranging trial to evaluate efficacy and safety in patients with irritable bowel syndrome with constipation (IBS-C). American Journal of Gastroenterology 2014:S541.
36. Wade PR, Palmer JM, McKenney S, et al. Modulation of gastrointestinal function by MuDelta, a mixed micro opioid receptor agonist/ micro opioid receptor antagonist. Br J Pharmacol 2012;167:1111-25.
37. Dove LS, Lembo A, Randall CW, et al. Eluxadoline benefits patients with irritable bowel syndrome with diarrhea in a phase 2 study. Gastroenterology 2013;145:329-38 e1.
38. Lembo AJ, Lacy BE, Zuckerman MJ, et al. Eluxadoline for Irritable Bowel Syndrome with Diarrhea. N Engl J Med 2016;374:242-53.
40. Lembo A, Pimentel M, Rao SS, et al. Repeat Treatment With Rifaximin Is Safe and Effective in Patients With Diarrhea-Predominant Irritable Bowel Syndrome. Gastroenterology 2016;151:1113-1121.
41. Pimentel M, Lembo A, Chey WD, et al. Rifaximin therapy for patients with irritable bowel syndrome without constipation. The New England journal of medicine 2011;364:22-32.
42. Schoenfeld P, Pimentel M, Chang L, et al. Safety and tolerability of rifaximin for the treatment of irritable bowel syndrome without constipation: a pooled analysis of randomised, double-blind, placebo-controlled trials. Aliment Pharmacol Ther 2014;39:1161-8.
43. Camilleri M, Bharucha AE, Ueno R, et al. Effect of a selective chloride channel activator, lubiprostone, on gastrointestinal transit, gastric sensory, and motor functions in healthy volunteers. Am J Physiol Gastrointest Liver Physiol 2006;290:G942-7.
44. Drossman DA, Chey WD, Johanson JF, et al. Clinical trial: lubiprostone in patients with constipation-associated irritable bowel syndrome--results of two randomized, placebo-controlled studies. Alimentary pharmacology & therapeutics 2009;29:329-41.
45. Chey WD, Drossman DA, Johanson JF, et al. Safety and patient outcomes with lubiprostone for up to 52 weeks in patients with irritable bowel syndrome with constipation. Alimentary pharmacology & therapeutics 2012;35:587-99.
46. Chapman RW, Stanghellini V, Geraint M, et al. Randomized clinical trial: macrogol/PEG 3350 plus electrolytes for treatment of patients with constipation associated with irritable bowel syndrome. The American journal of gastroenterology 2013;108:1508-15.
47. Ford AC, Moayyedi P, Lacy BE, et al. American College of Gastroenterology monograph on the management of irritable bowel syndrome and chronic idiopathic constipation. Am J Gastroenterol 2014;109 Suppl 1:S2-26; quiz S27.
48. Lembo A, Zakko SF, Ferreira NL, et al. Rifaximin for the Treatment of Diarrhea-Associated Irritable Bowel Syndrome: Short Term Treatment Leading to Long Term Sustained Response. Gastroenterology 2008;134:A-545.
49. Jarcho JM, Chang L, Berman M, et al. Neural and psychological predictors of treatment response in irritable bowel syndrome patients with a 5-HT3 receptor antagonist: a pilot study. Aliment Pharmacol Ther 2008;28:344-52.
50. Tong K, Nicandro JP, Shringarpure R, et al. A 9-year evaluation of temporal trends in alosetron postmarketing safety under the risk management program. Therap Adv Gastroenterol 2013;6:344-57.
51. Camilleri M, Mayer EA, Drossman DA, et al. Improvement in pain and bowel function in female irritable bowel patients with alosetron, a 5-HT3 receptor antagonist. Alimentary pharmacology & therapeutics 1999;13:1149-59.
52. Camilleri M, Northcutt AR, Kong S, et al. Efficacy and safety of alosetron in women with irritable bowel syndrome: a randomised, placebo-controlled trial. Lancet 2000;355:1035-40.
53. Chang L, Ameen VZ, Dukes GE, et al. A dose-ranging, phase II study of the efficacy and safety of alosetron in men with diarrhea-predominant IBS. Am J Gastroenterol 2005;100:115-23.
54. Krause R, Ameen V, Gordon SH, et al. A randomized, double-blind, placebo-controlled study to assess efficacy and safety of 0.5 mg and 1 mg alosetron in women with severe diarrhea-predominant IBS. Am J Gastroenterol 2007;102:1709-19.
55. Bardhan KD, Bodemar G, Geldof H, et al. A double-blind, randomized, placebo-controlled dose-ranging study to evaluate the efficacy of alosetron in the treatment of irritable bowel syndrome. Aliment Pharmacol Ther 2000;14:23-34.
56. Camilleri M, Chey WY, Mayer EA, et al. A randomized controlled clinical trial of the serotonin type 3 receptor antagonist alosetron in women with diarrhea-predominant irritable bowel syndrome. Arch Intern Med 2001;161:1733-40.
57. Lembo T, Wright RA, Bagby B, et al. Alosetron controls bowel urgency and provides global symptom improvement in women with diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2001;96:2662-70.
58. Chey WD, Chey WY, Heath AT, et al. Long-term safety and efficacy of alosetron in women with severe diarrhea-predominant irritable bowel syndrome. Am J Gastroenterol 2004;99:2195-203.
59. Lavo B, Stenstam M, Nielsen AL, et al. Loperamide in treatment of irritable bowel syndrome-a double-blind placebo controlled study. Scand Suppl 1987;130 SRC - GoogleScholar:77-80.
60. Hovdenak N. Loperamide treatment of the irritable bowel syndrome. Scandinavian journal of gastroenterology. Supplement 1987;130:81-4.
61. Drossman DA, Hasler WL. Rome IV-Functional GI Disorders: Disorders of Gut-Brain Interaction. Gastroenterology 2016;150:1257-61.
62. Drossman DA, Tack J, Ford AC, et al. Neuromodulators for Functional Gastrointestinal Disorders (Disorders of Gut-Brain Interaction): A Rome Foundation Working Team Report. Gastroenterology 2018;154:1140-1171 e1.
63. Vahedi H, Merat S, Momtahen S, et al. Clinical trial: the effect of amitriptyline in patients with diarrhoea-predominant irritable bowel syndrome. Alimentary pharmacology & therapeutics 2008;27:678-84.
64. Tack J, Broekaert D, Fischler B, et al. A controlled crossover study of the selective serotonin reuptake inhibitor citalopram in irritable bowel syndrome. Gut 2006;55:1095-103.
65. Kuiken SD, Tytgat GN, Boeckxstaens GE. The selective serotonin reuptake inhibitor fluoxetine does not change rectal sensitivity and symptoms in patients with irritable
66. Ladabaum U, Sharabidze A, Levin TR, et al. Citalopram provides little or no benefit in nondepressed patients with irritable bowel syndrome. Clin Gastroenterol Hepatol 2010;8:42-48 e1.
67. Masand PS, Pae CU, Krulewicz S, et al. A double-blind, randomized, placebo-controlled trial of paroxetine controlled-release in irritable bowel syndrome. Psychosomatics 2009;50:78-86.
68. Tabas G, Beaves M, Wang J, et al. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. The American journal of gastroenterology 2004;99:914-20.
69. Talley NJ, Kellow JE, Boyce P, et al. Antidepressant therapy (imipramine and citalopram) for irritable bowel syndrome: a double-blind, randomized, placebo-controlled trial. Dig Dis Sci 2008;53:108-15.
70. Tabas G, Beaves M, Wang J, et al. Paroxetine to treat irritable bowel syndrome not responding to high-fiber diet: a double-blind, placebo-controlled trial. Am J Gastroenterol 2004;99:914-20.
71. Grover M, Drossman DA. Psychotropic agents in functional gastrointestinal disorders. Curr Opin Pharmacol 2008;8:715-23.
72. Khalif IL, Quigley EM, Makarchuk PA, et al. Interactions between symptoms and motor and visceral sensory responses of irritable bowel syndrome patients to spasmolytics (antispasmodics). J Gastrointestin Liver Dis 2009;18:17-22.
73. Ruepert L, Quartero AO, de Wit NJ, et al. Bulking agents, antispasmodics and antidepressants for the treatment of irritable bowel syndrome. Cochrane Database Syst Rev 2011:CD003460.
74. Palsson OS, Whitehead WE, van Tilburg MA, et al. Rome IV Diagnostic Questionnaires and Tables for Investigators and Clinicians. Gastroenterology 2016.
75. Administration FaD. Guidance for Industry, Patient Reported Outcomes: Use in Medical Product Development to Support Labeling Claims. 2005. https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf
76. Ballou S, Beath A, Kaptchuk TJ, et al. Factors associated with response to placebo in patients with irritable bowel syndrome and constipation. Clin Gastroenterol Hepatol 2019;in press.
77. Quigley EMM, Tack J, Chey WD, et al. Randomised clinical trials: linaclotide phase 3 studies in IBS-C - a prespecified further analysis based on European Medicines Agency-specified endpoints. Alimentary pharmacology & therapeutics 2013;37:49-61.